TWI648250B - New crystal form of sacubitril sodium salts - Google Patents

Abstract

The present invention relates to the field of pharmaceutical synthesis, in particular to the new crystalline forms A, B, C, D and E of the sulbactam sodium salt and to a process for the preparation thereof.

Description

Shakubite sodium salt new crystal form

The present invention relates to the field of pharmaceutical synthesis, in particular to the new crystalline forms A, B, C, D and E of the sulbactam sodium salt and to a process for the preparation thereof.

Sacubitril, chemical name 4-{[(2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl -5-oxopentan-2-yl]amino}-4-oxobutanoic acid, an enkephalinase inhibitor, has the structure shown below: .

Enkephalinase (NEP) is a metalloproteinase that is expressed in many tissues in the body and has the most renal expression. It can catalyze the degradation of various endogenous peptides, such as NP, bradykinin, substance P, etc. Therefore, NEP inhibitors The amount of urinary natriuretic peptide (NP) can be increased. NP plays an important role in body fluid balance. NP has three subtypes, type A (ANP), type B (BNP) and type C (CNP). When the blood vessel volume overload causes an atrial pressure increase, the atrium releases ANP, which is also called atrial natriuretic peptide. Increased left ventricular filling pressure can promote the release of BNP. ANP and BNP have the effects of relaxing blood vessels and discharging sodium and diuresis. CNP is mainly expressed in the central nervous system, kidney and vascular endothelial cells, and has an antithrombotic effect. Excessive plasma volume and left ventricular filling pressure can stimulate the release of NP, and the up-regulation of NP in patients with heart failure is particularly evident. Direct vasodilation of NP reduces ventricular preload, systemic vascular resistance, and arterial pressure. NP can exert direct vasodilation by reducing ventricular preload, systemic vascular resistance, and arterial pressure. In addition, NP can also increase the filtration rate of glomeruli and promote sodium and water excretion. NP also reduces the release of renin, reduces the amount of plasma angiotensin II, and relaxes blood vessels.

Angiotensin II (Ang II) is a potent vasoconstrictor and is the most important active hormone in the renin-angiotensin-aldosterone system (RAAS). It plays a major role in cardiovascular disease and exerts a direct boosting effect. There are at least two subtypes of AngII receptors, AT1 and AT2. AngII is highly selective for the AT1 receptor and 300 times higher than the AT2 receptor. When AngII binds to the AT1 receptor, it activates the corresponding cell channel, thereby showing the main effects of AngII, such as vasoconstriction, aldosterone secretion, renal tubular sodium, and water reabsorption. AT1 receptor antagonists can inhibit AngII-mediated vasoconstriction, as well as renal tubular sodium and water reabsorption; and inhibit the regulation of RAAS on baroreceptors and inhibit sympathetic excitation. AT1 receptor antagonists have been widely used in the treatment of hypertension.

When the combination of Shakubiqu or its salt with angiotensin II AT1 receptor antagonist, such as valsartan, can simultaneously inhibit enkephalinase and angiotensin receptor, which can simultaneously act on the kidney. The vasopressin system promotes brain natriuretic peptides and acts in a variety of ways on the neuroendocrine system of the heart, blocking receptors that exert harmful effects, and promoting protective mechanisms. LCZ-696 (Entresto) developed by Novartis, which is a eutectic composed of sulcoate sodium and valsartan disodium, is used for the treatment of chronic heart failure and/or hypertension, with remarkable effects and good safety. Now the drug has been approved for new drug marketing in the United States, the European Union and other countries, and has been approved by the FDA, becoming the first new drug approved for chronic heart failure in the past 10 years.

Novartis developed sulphate sodium and valsartan disodium into eutectic LCZ-696. One of the reasons is that LCZ-696 is less hygroscopic than sacurbita sodium, which is more conducive to production and storage. Although the LCZ-696 eutectic has improved in physical properties, it has a fixed composition ratio, which limits the ratio of sulbactam to different ratios of valsartan or its pharmaceutically acceptable salt, or other AT1 receptor antagonists. Combination medication is not conducive to clinical adjustment according to different conditions. Shakubite free acid is not suitable for use in preparations, especially oral solid preparations, because of its low melting point and poor water solubility. The amorphous form of the sulphate sodium salt is highly hygroscopic and difficult to prepare. U.S. Patent 5,217,996 discloses a solid form of shakupitide sodium salt X, which is prepared according to the method, and is found to have a high hygroscopicity. Therefore, it is necessary to further study the solid form of the Shakubite sodium salt in order to obtain the Shakubite sodium salt with simple preparation process and improved physical properties such as hygroscopicity.

It has been confirmed that it is very difficult to form a sulbactam sodium salt having the desired advantageous properties, and in most cases, a sodium salt form having poor stability is obtained, and studies have shown that the sandbox of the present invention is particularly specific to the sodium sulphate crystal form. advantageous.

It is an object of the present invention to provide crystal forms A, B, C, D and E of the sulbactam sodium salt.

Another object of the present invention is to provide a process for the preparation of crystalline forms A, B, C, D and E of the sulbactam sodium salt.

The crystal form A of the sulphate sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed by degree 2θ is about 6.0±0.2, 7.0±0.2, 11.8±0.2. , 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± 0.2 with peaks; preferably at about 6.0 ± 0.2, 7.0 ± 0.2, 11.8 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 23.5 ± There is a peak at 0.2.

In a specific embodiment, the shakubic sodium salt crystal form A has an endothermic peak at a temperature close to 168 ° C at a heating rate of 10 ° C / min.

In a specific embodiment, the shakubic sodium salt crystal form A has an endothermic peak at 166-169 ° C at a heating rate of 10 ° C / min.

In a specific embodiment, the Shakusone sodium salt crystal form A has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, at a heating rate of 10 ° C/min, the Shakushim sodium salt crystal form A has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG.

The DSC chart of Shakuto's crystal form A shows an endothermic peak at around 166 °C with a 焓 value of 98.31 J/g. The higher endothermic peak temperature and enthalpy value indicate that the crystal lattice of the crystal form has high stability. It is worth noting that the crystal form is maintained in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours and a water absorption of 1.4%, while the amorphous form under the same conditions has a high degree of water absorption. 12.8%.

The crystalline form B of the sacuronium sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 5.1 ± 0.2, 10.4 ± 0.2, 11.2 ± 0.2, 19.2±0.2, 19.7±0.2, 21.3±0.2, 21.8±0.2 have peaks; preferably about 5.1±0.2, 8.6±0.2, 10.4±0.2, 11.2±0.2, 12.1±0.2, 19.2±0.2, 19.7 There are peaks at ±0.2, 21.3±0.2, and 21.8±0.2.

In one embodiment, the crystalline form B of the sulbactam sodium salt has an endothermic peak at a heating rate of 10 ° C / min at a temperature close to 133 ° C and near 159 ° C.

In a specific embodiment, the crystalline form B of the sulbactam sodium salt has an endothermic scanning calorimetry at 130-134 ° C and 149-160 ° C at a heating rate of 10 ° C / min. peak.

In a specific embodiment, the shakusone sodium salt crystal form B has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

In one embodiment, at a heating rate of 10 ° C/min, the shakupyr sodium salt crystal form B has an endothermic curve substantially the same as the differential thermal analysis endothermic curve shown in FIG.

The crystal form C of the sulphonic sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2 , 19.3 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2 with peaks; preferably about 6.5 ± 0.2, 10.5 ± 0.2, 11.2 ± 0.2, 12.7 ± 0.2, 14.5 ± 0.2, 16.8 ± 0.2, 19.3 ± 0.2, 21.4 ± There are peaks at 0.2, 22.0 ± 0.2, and 27.2 ± 0.2.

In one embodiment, the sulphate sodium salt crystal form C has a melting point of about 136 ± 5 °C.

In a specific embodiment, the shakusone sodium salt crystal form C has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

It is worth noting that the crystal form is maintained in an open container at a temperature of 25 ° C and a relative humidity of 43.5% for 3 hours and a water absorption of 2.4%, while the amorphous form under the same conditions has a high degree of water absorption. 12.8%.

The crystal form D of the sulphonic sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 5.2 ± 0.2, 8.7 ± 0.2, 10.4 ± 0.2. There are peaks at 12.2±0.2 and 15.7±0.2.

In one embodiment, the sulphate sodium salt form D has a melting point of about 117 ± 5 °C.

In a specific embodiment, the shakusone sodium salt crystal form D has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

The crystal form E of the sulphonic sodium salt provided by the present invention is characterized in that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed by degree 2θ is about 8.2 ± 0.2, 10.4 ± 0.2, 11.0 ± 0.2. There are peaks at 13.9±0.2, 16.7±0.2, and 21.3±0.2.

In one embodiment, the sulphonic sodium salt crystal form E has a melting point of about 130 ± 5 °C.

In a specific embodiment, the shakusone sodium salt crystal form E has a powder X-ray diffraction spectrum substantially the same as the powder diffraction pattern shown in FIG.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A, B, C, D or E of the Sacurbitium sodium salt of the present invention in admixture with a pharmaceutically acceptable carrier. The pharmaceutical composition may be administered parenterally or non-pharmaceutically. For gastrointestinal administration, it can be administered to a patient in the form of tablets, capsules, solutions, suspensions and the like.

The crystalline form A, B, C, D or E of the sacuronium salt of the present invention, or a pharmaceutical composition comprising the same, can be used, for example, for the prevention or treatment of a disease or condition associated with enkephalinase.

The main applications include heart failure, high blood pressure, and cardiomyopathy.

Those of ordinary skill in the art are well able to select relevant standard animal experimental models to demonstrate the therapeutic indications and benefits indicated by the context.

In the present invention, "the same powder X-ray diffraction spectrum" means that the positions of the peaks represented by degrees 2θ are substantially the same, and the relative intensities of the peak positions are substantially the same. The relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the strongest peak when the intensity of the peak with the highest intensity among all the diffraction peaks of the powder X-ray diffraction spectrum is 100%. It should be noted that the 2θ angle in the diffraction spectrum of the X-ray powder may sometimes cause some measurement errors due to various factors, and the measured value may usually be ±0.3, preferably ±0.2, more preferably ±0.1. The degree of change. Therefore, in the present specification, the 2θ angle based on the measured value of a specific sample is understood to include the meaning of these allowable errors. In the present invention, "substantially the same as the powder X-ray diffraction pattern shown in FIG. 1" means at least 50%, or at least 60%, or at least 70%, or at least 80% of the powder X-ray diffraction spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern.

In addition, the absorption peak in the differential scanning calorimetry is inherent in physical properties of the crystal forms of the present invention. However, in actual measurement, in addition to measurement errors, impurities may be mixed in an allowable amount. The reason is that the melting point changes, and this possibility cannot be denied. Therefore, those skilled in the art can fully understand to what extent the measured value of the endothermic peak temperature in the present invention can be varied. For example, the conceivable error is, in some cases, about ±5 ° C. Preferably, it is about ± 3 ° C, more preferably about ± 2 ° C, and even more preferably about ± 1 ° C.

The "melting point" in the present invention means the initial melting temperature at which the crystal form is melted.

Analytical methods used in the present invention:

(1) X-ray powder diffraction

Using a Bruker D8 advance diffractometer, use a Cu Ka fill tube (40 kV, 40 mA) at room temperature as an X-ray source with a wide-angle goniometer, a 0.6 mm divergence slit, a 2.5° primary cable slit, 2.5° Staged slot, 8 mm anti-scatter slit, 0.1 mm detector slit and LynxEye detector. In the 2θ continuous scan mode, data acquisition was performed at a scan speed of 2.4°/min and a scan step of 0.02° in the range of 3°-40°.

(2) Differential scanning calorimeter

Data acquisition was performed using TA Q200 and Mettler DSC 1+ under N2 protection at a flow rate of 50 mL/min and warming from room temperature to degradation temperature at 10 °C/min.

(3) Thermogravimetric analyzer

Data acquisition was accomplished using TA Q500 at a flow rate of 50 mL/min under N ₂ protection from 10 ° C/min to room temperature to 30% or less.

The above summary of the present invention will be further described in detail by the embodiments of the present invention. However, it should be understood that the present invention is limited to the following embodiments. The scope of the invention.

Comparative Example 1: Preparation of Shakubite Sodium Salt X

The sulbactam sodium salt X was prepared by the method of Example 1 of US 5,217,996, and the resulting sulphonic acid sodium salt X had a melting point of 159-160 °C.

Comparative Example 2: Preparation of amorphous sandboxed sodium salt

1.0 g of sirloin free acid was suspended in 10 mL of water, aqueous sodium hydroxide solution (97 mg / 1 mL) was added dropwise, and the mixture was stirred at room temperature for 0.5 h, and the solution was lyophilized to give a white powdery solid.

Example 1: Preparation of Shakubite Sodium Salt Form A

Dissolve 112 mg of sulbacb in 2 mL of ethanol, add 0.1 mL of ethanol solution containing 10.9 mg of sodium hydroxide, stir for 0.5 hour, and concentrate under reduced pressure to give the residue as ethanol / n-heptane (1/19) , volume ratio) 300 mL suspension stirring overnight, filtered, and dried under vacuum at 40 ° C to give a solid. The solid was added to 10 mL of isopropanol, and after stirring for 72 hours, the supernatant was centrifuged, and the solid was dried in an oven at 40 ° C to obtain a white solid, i.e., type A shakupitr sodium salt.

Solid-state characterization of the Shakubite sodium salt crystal form A by X-ray powder diffraction and differential scanning calorimetry, the solid state characterization parameters and maps are as described herein.

The melting point of the type A shaku sulphate salt at around 167-168 ° C was measured by a melting point meter.

Example 2: Preparation of Shakubite Sodium Salt Form B

112 mg of sulbacb was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of the dried solid was dissolved in 0.6 mL of ethanol, and the small glass bottle in which the solution was placed was sealed with a sealing film, and the hole was punched, placed in a glass bottle containing 5 mL of ethyl acetate, and the cap was screwed. After standing at room temperature for 15 days, the small glass bottle was taken out, and the supernatant was centrifuged to obtain a white solid, that is, B-type shakupitide sodium salt.

The solid form characterization parameters and maps of the sulbactam sodium salt form B were characterized by X-ray powder diffraction and differential scanning calorimetry.

The melting point of the B-type shaku-salt sodium salt was about 133-136 ° C as measured by a melting point apparatus.

Example 3: Preparation of Shakubite Sodium Salt Form C

112 mg of sirolimus was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, and the mixture was stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of the dried solid was added to 1 mL of isopropanol, and after stirring for 72 hours, the supernatant was centrifuged, and the solid was dried in an oven at 40 ° C to obtain a white solid, that is, C-type shakupitide sodium. salt.

Solid-state characterization of the Shakubite sodium salt crystal form C by X-ray powder diffraction, the solid state characterization parameters and maps are as described herein.

The melting point of C-type shaku-salt sodium salt at about 136±5 °C was measured by the melting point meter.

Example 4: Preparation of Shakubite Sodium Salt Form D

112 mg of sulbacb was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of this solid was added to 1 mL of 3-pentanone. After stirring for 72 hours, the supernatant was centrifuged, and the solid was dried in an oven at 40 ° C to obtain a white solid, ie, D-type shakupitide sodium. salt.

The solid form characterization parameters and maps of the sulbactam sodium salt form D were characterized by X-ray powder diffraction.

The melting point of the D-type shaku-salt sodium salt at about 117±5 °C was measured by the melting point meter.

Example 5: Preparation of Shakubite Sodium Salt Crystal Form E

112 mg of sulbacb was dissolved in 2 mL of ethanol, and an ethanol solution containing 9.29 mg of sodium hydroxide per 0.5 mL was added dropwise, stirred for 0.5 hour, and concentrated under reduced pressure to give a dry solid. 30 mg of the dried solid was added to 1 mL of 2-butanone, dissolved, and ethyl acetate was added dropwise until turbidity appeared. The turbid liquid was centrifuged to discard the supernatant, and the solid was placed in an oven at 40 ° C to dry. White solid, ie E-type shakupitide sodium salt.

Solid-state characterization of the Shakubite sodium salt crystal form E by X-ray powder diffraction, the solid state characterization parameters and maps are as described herein.

E-type shaku-salt sodium salt melted at 130±5 °C as measured by a melting point apparatus.

Example 6 Determination of the hygroscopicity of the crystal form of each of the Sacurbitium sodium salts in the present invention

test methods:

1. Take the dry-filled glass weighing bottle (outer diameter 50mm, height 15mm) and place it in the artificial climate chamber (set temperature 25±1°C, relative humidity 43.5±2%) on the previous day, weigh (m1).

2. Take the appropriate amount of the crystal form of the present invention, place it in the above weighing bottle and lay it in the weighing bottle. The thickness of the test sample is generally about 1 mm and weighed (m2).

3. Open the weighing bottle and place it in constant temperature and humidity (set temperature is 25±1°C, relative humidity is 43.5±2%).

4. Cover the weighing bottle cap before weighing, weigh (m3), calculate the percentage of water absorption at each time point, and the percentage of water absorption = (m3-m2) / (m2-m1) × 100%.

Results: Table 1

From the hygroscopicity data of Table 1, it can be seen that the crystalline form of the present invention has a significantly improved water absorption capacity compared to the amorphous form of the Shakubiqu sodium salt, and the Shakubites sodium salt X disclosed in the literature is suitable for further development.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make several improvements and retouchings without departing from the spirit of the present invention. It should also be considered as the scope of protection of the present invention.

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Figure 1 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form A.

Figure 2 is a differential scanning calorimetry chart (DSC chart) of the Shakubite sodium salt crystal form A.

Figure 3 is a powder X-ray diffraction pattern (XRD pattern) of Shakubite sodium salt crystal form B.

Figure 4 is a differential scanning calorimetry chart (DSC chart) of the Shakupitetine sodium salt form B.

Figure 5 is a thermogravimetric analysis chart (TGA chart) of the Shakubite sodium salt crystal form B.

Figure 6 is a powder X-ray diffraction pattern (XRD pattern) of the Shakubite sodium salt crystal form C.

Figure 7 is a powder X-ray diffraction pattern (XRD pattern) of the Shakubite sodium salt crystal form D.

Figure 8 is a powder X-ray diffraction pattern (XRD pattern) of the Shakubite sodium salt crystal form E.

Claims (6)

A sulphate sodium salt crystal form B, wherein the crystal form has the property that it uses Cu-Ka radiation, and the diffraction spectrum of the X-ray powder expressed in degrees 2θ is about 5.1 ± 0.2, 10.4 ± 0.2, 11.2 ± There are peaks at 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 21.3 ± 0.2, and 21.8 ± 0.2. As shown in claim 1, the Sacurbitium sodium salt crystal form B, wherein the differential scanning calorimetry has an endothermic peak at a temperature close to 133 ° C and close to 159 ° C at a heating rate of 10 ° C / min. As shown in claim 1, the Sacurbitium sodium salt crystal form B, wherein the differential scanning calorimetry has an endothermic peak at 130-134 ° C and 149-160 ° C under the heating rate of 10 ° C / min. A pharmaceutical composition comprising the crystalline form of the Shakubite sodium salt of any one of claims 1 to 3 and a pharmaceutically acceptable carrier. A use of a Shakubi crystal form as claimed in any one of claims 1 to 3 for the preparation of a medicament for treating an enkephalinase-related disease. The use of claim 5, wherein the disease comprises heart failure, hypertension, and cardiomyopathy.